The ability of the auditory system to encode the frequency, localization and intensity of sounds, and to discriminate between small differences in these parameters, depends on the precise timing and frequency of action potentials in neurons within central auditory pathways. These, in turn, depend on the number and characteristics of plasma membrane ion channels in these neurons, particularly potassium channels, which control factors such as threshold, latency to action potential accommodation, and pattern of firing in response to a maintained stimulus. In preliminary experiments, we have found that a recently cloned potassium channel gene, Kv3.1, is expressed at very high levels in neurons of central auditory pathways. Using in situ hybridization, the polymerase chain reaction, immunohistochemistry and other molecular biological approaches, we plan to identify other channels that are expressed in these pathways and to localize the channels to specific auditory nuclei and neuronal subtypes. Because the response properties of auditory neurons change during development, we shall determine the stages in development at which each channel species appears. We shall then measure the influence of auditory stimulation or deprivation on the level of expression of the channels. To determine which component of potassium current each gene corresponds to, we shall, using patch clamp recording, compare the electrical characteristics of the channels expressed in cell lines of Xenopus oocytes with those found in auditory neurons. This will be tested further by electrophysiological experiments that use immunological techniques and antisense oligonucleotide approaches to selectively alter the channel within auditory neurons. Finally, using brain slices and primary cultures of auditory neurons, we shall determine whether the expression of the genes for these channels are regulated by factors such as depolarization, ongoing electrical activity, growth factors and second messengers. An understanding of the molecular basis for the electrical characteristics of different neurons in the auditory system is likely to lead to an understanding od deficits in certain forms of deafness and in the genesis of abnormal firing patterns such as occur in audiogenic seizures.
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